SLP-76 binding to p56lck:: A role for SLP-76 in CD4-induced desensitization of the TCR/CD3 signaling complex

Nonreceptor protein tyrosine kinases and associated substrates play a pivotal role in Ag receptor stimulation of resting cells and in the initiation of activation-induced cell death (AICD) of preactivated T cells. CD4-associated p56lck has been implicated not only in the activation of primary T cells; but also in the inhibition of T cell responses. We have previously shown that CD4(+) T cell clones can be rescued from AICD when surface CD4 is engaged before the TCR stimulus. In this study, we show that prevention of AICD is associated with a CD4-dependent inhibition of TCR-triggered tyrosine phosphorylation of the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and Vav, We provide evidence for a SLP-76 interaction with Src homology 3 domains of p56(lck) and identify amino acids 185-194 of SLP-76 as relevant docking site. In view of the multiple functions of p56(lck) and SLP-76/Vav in the initiation of TCR/CD3/CD4 signaling, we propose a model for the CD4-dependent inhibition of TCR signaling and AICD of preactivated T cells. Our data suggest that preformed activation complexes of adapter proteins and enzymes in the vicinity of the CD4/p56(lck) complex are no longer available for the TCR signal when CD4 receptors are engaged before TCR stimulation.